Oral Octreotide for the Treatment of Disease

This application claims priority to U.S. Ser. No. 62/281,320, filed Jan. 21, 2016; U.S. Ser. No. 62/299,607, filed Feb. 25, 2016; and, U.S. Ser. No. 62/303,072, filed Mar. 3, 2016; the contents of each of which is incorporated herein by reference.

The present invention relates to oral delivery of octreotide alone and in combination with other therapeutic agents for the treatment of various diseases including polycystic disease (polycystic kidney disease, polycystic liver disease, polycystic ovarian syndrome), hypotension especially neurogenic orthostatic hypotension and postprandial hypotension, intractable diarrhea of various types, neuroendocrine tumors and carcinoid syndrome.

The use in clinical trials of injectable octreotide or lanreotide—which are somatostatin receptor ligands (SRLs)—for the treatment of various diseases e.g. polycystic liver disease and polycystic kidney disease is described in the literature. See Lariviere et al 2015, Translational Research, 165 (4), 488-498, Elsevier Inc; Chapman et al (2015) Kidney International, 17-27; Chandok (2012) Annals of Hepatology, 11 (6), 819-826; and Cnossen and Drenth (2014) Orphanet Journal of Rare Diseases, 9, 69. Neuroendocrine tumors and carcinoid syndrome are described in the literature e.g. Kloppel et al 2004, Ann. N.Y. Acad Sci, 1014:13-17. Combination treatment of injectable octreotide or lanreotide with other therapeutic agents for treatment of neuroendocrine tumors and carcinoid syndrome is described in the literature. Examples are Oberg et al 2004, Annals of Oncology 15:966-973; Oberg et al 2012, Annals of Oncology 23 (Supplement 7): vii124-vii130; Strosberg et al (2017) New England J Med, 376:2, 125-135; and Pavel et al (2016) Clin. Pharmacol and Therapeutics advance online publication doi:10.1002/cpt.559. Injectable octreotide has been used for intractable/refractory diarrhea and this has been reviewed by Szilagyi and Shrier (2001) Aliment Pharmacol Ther. 15:1889-1897. Treatment of secretory diarrhea in general has been reviewed by Thiagarajah and Donowitz (2015) Aug; 12 (8): 446-57. Guidelines for treatment of cancer-treatment induced diarrhea have been described by Benson et al (2004) J. of Clin. Oncology,22 (14), 2918-2926. Injectable octreotide has been used for management of short bowel syndrome and this has been described by Nehra et al (2001) Am. J. of Gastroenterology, 96 (5),1484-1498; treatment of short bowel syndrome has been discussed by Parrish et el (March 2015) Practical Gastroenterology, 28-42. Injectable octreotide has been used for management of dumping syndrome and this has been described by Didden et al (2006) Aliment Pharmacol Ther, 24:1367-1375. Injectable octreotide has been used for management of diarrhea in HIV-infected individuals and this has been described by MacArthur and DuPont (2012) Clinical Infectious Diseases,55 (6): 860-867.

There is a need for use of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide alone and in combination treatment with other therapeutic agents for the treatment of various diseases including polycystic disease (for example polycystic kidney disease, polycystic liver disease, polycystic ovarian syndrome), hypotension especially neurogenic orthostatic hypotension and postprandial hypotension, intractable diarrhea of various types, neuroendocrine tumors and carcinoid syndrome. Particular advantages of oral administration are avoidance of often painful injections, avoidance of injection site reactions and reduction in breakthrough symptoms.

The present invention relates to therapy of a subject suffering from polycystic disease (for example polycystic kidney disease and/or polycystic liver disease or other diseases such as polycystic ovarian syndrome), hypotension especially neurogenic orthostatic hypotension and postprandial hypotension, intractable diarrhea of various types, neuroendocrine tumors and carcinoid syndrome. The method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide.

Additionally, the present invention relates to combination therapy of a subject suffering from these diseases. One method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of a second and optionally a third therapeutic agent.

For example, one method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of an angiotensin-converting enzyme inhibitor e.g. lisinopril, administered orally. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of an angiotensin receptor blocker (also termed angiotensin II receptor antagonist) e.g. telmisartan (Micardis™) administered orally. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of an arginine vasopressin V2 receptor antagonist e.g. tolvaptan, administered orally. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of a statin e.g. pravastatin administered orally. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of an Src kinase inhibitor (also termed a tyrosine kinase inhibitor) e.g. bosutinib, administered orally; bosutinib is marketed under the trade name Bosulif®. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of an mTOR inhibitor e.g. everolimus, administered orally (Afinitor® of Novartis) or sirolimus, also termed rapamycin (Rapamune® of Pfizer) administered orally. Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of a drug which treats diarrhea e.g. loperamide, cholestyramine, atropine or an opioid (e.g. codeine, diphenoxyate or difenoxin). Another method of treatment comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) e.g. oral octreotide in combination with a therapeutically effective amount of teduglutide or L-glutamine.

Oral octreotide may also be administered in combination with injectable octreotide to control breakthrough symptoms.

Another aspect of this invention is a unit dosage formulation for oral administration comprising a therapeutically effective amount of octreotide and a therapeutically effective amount of an angiotensin-converting enzyme inhibitor; in a particular aspect the angiotensin—converting enzyme inhibitor is lisinopril. Another aspect of this invention is a unit dosage formulation for oral administration comprising a therapeutically effective amount of octreotide and a therapeutically effective amount of an angiotensin receptor blocker; in a particular aspect the angiotensin receptor blocker is telmisartan. Another aspect of this invention is a unit dosage formulation for oral administration comprising a therapeutically effective amount of octreotide and a therapeutically effective amount of an arginine vasopressin V2 receptor antagonist; in a particular aspect the arginine vasopressin V2 receptor antagonist is tolvaptan. Another aspect of this invention is a unit dosage formulation for oral administration comprising a therapeutically effective amount of octreotide and therapeutically effective amount of a statin; in a particular aspect the statin is pravastatin. Another aspect of this invention is a unit dosage formulation for oral administration comprising octreotide and a Src kinase inhibitor; in a particular aspect the Src kinase inhibitor is bosutinib. Another aspect of this invention is a unit dosage formulation for oral administration comprising a therapeutically effective amount of octreotide and a a therapeutically effective amount of mTOR inhibitor; in a particular aspect the mTOR inhibitor is everolimus or sirolimus (also termed rapamycin). Additionally, the unit dosage formulation for oral administration may include a therapeutically effective amount of octreotide plus a therapeutically effective amount of two or more additional drugs selected from an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, an arginine vasopressin V2 receptor antagonist, statin, Src kinase inhibitor and mTOR inhibitor. Additionally, a unit dosage formulation for oral administration may include a therapeutically effective amount of octreotide plus a therapeutically effective amount of one or more additional drugs selected from loperamide, cholestyramine, atropine, an opioid (e.g. codeine, diphenoxylate or difenoxin), teduglutide, L-glutamine and telotristat etiprate.

The invention also relates to a method of treatment of a subject suffering from a neuroendocrine tumor which comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) in combination with a therapeutically effective amount of one or more anti-tumor agents or an mTOR inhibitor or an VEGFR inhibitor or an Src kinase inhibitor or a tryptophan hydroxylase inhibitor or an injectable somatostatin receptor ligand (SRL) or telotristat etiprate.

Throughout this application, various publications, including United States patents, are referenced by author and year and patents and applications by number. The disclosures of these publications and patents and patent applications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which abnormal cysts develop and grow in the kidneys. Cystic disorders can express themselves at any point, infancy, childhood, or adulthood. The disease occurs in humans and some animals. PKD is characterized by the presence of multiple cysts (hence, “polycystic”) typically in both kidneys; however, 17% of cases initially present with observable disease in one kidney, with most cases progressing to bilateral disease in adulthood. Polycystic kidney disease is a general term for the two types of PKD, each having their own pathology and causes. The two types of PKD are autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), which differ in their mode of genetic inheritance.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the inherited cystic kidney diseases with an incidence of 1:500 live births. Studies show that 10% of end-stage kidney disease (ESKD) patients being treated with dialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.

Mutations in the PKD-1 and PKD-2 genes account for the overwhelming majority of ADPKD cases. Fewer than 10% of cases of ADPKD appear in non-ADPKD families. Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring kidney parenchyma, and progressively compromise kidney function, typically leading to kidney failure by the sixth decade of life. Kidneys can enlarge to 3 to 4 times their normal size.

Autosomal recessive polycystic kidney disease (ARPKD) is the less common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, the kidneys are often underdeveloped resulting in a 30% death rate in newborns with ARPKD.

Currently there are no Food and Drug Administration-approved treatments for polycystic kidney disease. Several drugs designed to slow or arrest the progression of polycystic kidney disease have shown promise in preclinical or in clinical trials. These include injectable SRLs and other drugs. A significant barrier to the development of an effective therapy for polycystic kidney disease has been the lack of a means to measure the progression of the disease. Serum creatinine is not usually increased until late in the course of the disease by which time significant and irreversible damage to the renal parenchyma has already occurred. Measurement of total kidney volume (TKV) in relation to age can identify a patient with progressive disease. TKV is an accurate estimate of kidney cyst burden as associated with pain, hypertension, gross hematuria, proteinuria or albuminuria, and loss of kidney function. TLV increases exponentially in virtually every ADPKD patient with an average of 5-6% per year in adults. Elevated TKV, particularly when used together with age and kidney function, identifies individuals who are at risk for progression to end stage renal disease (ESRD). See Lariviere et al 2015, Translational Research, 165 (4) 488-498, Elsevier Inc; and Chapman et al (2015) Kidney International, 17-27.

The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop in 2012 to examine critically available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR.

Polycystic liver disease comes in two forms as ADPKD (with kidney cysts) and ADPLD (liver cysts only). Liver cysts occur in more than 80% of adults with ADPKD. In the vast majority of patients, the liver cysts are asymptomatic but they can grow uncomfortably large and cause pain. Unlike the kidney failure that inevitably results from polycystic kidney disease, PLD does not normally lead to liver failure and, in fact, most patients do not require surgery. In a minority of patients, polycystic liver disease creates a myriad of symptoms from the compressive effect of enlarged cysts and can even cause malnutrition and liver decompensation in the severest of cases. In patients with symptomatic disease a variety of interventional radiology or surgical techniques can be considered, including aspiration with sclerotherapy of a dominant cyst, fenestration, segmental hepatic resection and even liver transplantation.

Currently there are no Food and Drug Administration-approved treatments for polycystic liver disease. Several drugs designed to slow or arrest the progression of polycystic liver disease have shown promise in preclinical or in clinical trials. These include injectable SRLs and other drugs. Total liver volume (TLV), total kidney volume (TKV) and changes in glomerular filtration rate may be measured. See Chandok (2012) Annals of Hepatology, 11 (6), 819-826; and Cnossen and Drenth (2014) Orphanet Journal of Rare Diseases, 9, 69.

Polycystic ovary syndrome (PCOS), one of the most common causes of ovulatory infertility, affects 4-7% of women. PCOS may have some genetic component and clinical features of this disorder may change throughout a life span, starting from adolescence to postmenopausal age. In young women with PCOS, hyperandrogenism, menses irregularities, and insulin resistance may occur together, emphasizing the pathophysiological role of excess androgen and insulin on PCOS. Hyperandrogenism and infertility represent the major complaints of PCOS in adult fertile age. In addition, obesity and metabolic syndrome may affect more than half these women. Later in life, it becomes clear that the association of obesity (particularly the abdominal phenotype) and PCOS renders affected women more susceptible to develop type 2 diabetes mellitus (T2DM), with some difference in the prevalence rates among countries, suggesting that environmental factors are important in determining individual susceptibility. Little is known about ovarian morphology and androgen production in women with PCOS after menopause. Some studies found that morphological ultrasonographic features consistent with polycystic ovaries are very common in postmenopausal women, and that these features are associated with higher than normal testosterone levels and metabolic alterations. (Pasquali 2006 Annals of the New York Academy of Sciences 1092(1):158-74⋅January 2007.)

Currently, there are no FDA-approved drugs that treat PCOS; treatments today are used off-label to treat one, or multiple, categories of PCOS-associated symptoms: uteroprotection, hyperandrogenism, fertility and metabolic health.

Neurogenic Orthostatic Hypotension (nOH) is a subtype of orthostatic hypotension that occurs in people with an existing neurologic disease (e.g., neurological conditions that are chronic and irreversible). In some embodiments, the neurologic disease is Parkinson's Disease or Multi-System Atrophy (MSA). Orthostatic (postural) hypotension refers to a reduction in systolic blood pressure (e.g., of at least 20 mm Hg) or a reduction in diastolic blood pressure (e.g., of at least 10 mm Hg) during the first 3 minutes of standing. Neurogenic orthostatic hypotension can be caused by autonomic nervous system malfunction, which is the part of the nervous system controlling involuntary body activity (e.g., keeping blood pressure normal). Symptoms include dizziness, light-headedness, syncope (fainting), fatigue, blurry vision, weakness, trouble concentrating, head and neck pain. Outcomes include injuries such as tooth damage, broken bones, even death as a result of falling.

Postprandial hypotension is commonly defined as a decrease in systolic blood pressure of 20 mmHg or more observed within two hours after meal ingestion. It is very common in older patients especially in those living in long-term healthcare homes. Patients with postprandial hypotension may develop symptomatic hypotension, syncope (fainting) and falls. See Lisk, R. (April 2010)in www.gerimed.co.uk, Cardiology 203-206; and Lubart et al (September 2006) Journal of the American Geriatrics Society, Vol. 54, Issue 9, pages 1377-1381,-

Diarrheal disease remains a major health burden worldwide. Secretory diarrheas are caused by certain bacterial and viral infections, inflammatory processes, drugs and genetic disorders. Fluid secretion across the intestinal epithelium in secretory diarrheas involves multiple ion and solute transporters, as well as activation of cyclic nucleotide and Ca2+ signalling pathways. Current treatment of diarrhea includes replacement of fluid and electrolyte losses using oral rehydration solutions, and drugs targeting intestinal motility or fluid secretion.

Diarrhea may have many causes and may be intractable (also termed refractory). It may be due to dumping syndrome, or to short bowel syndrome, or may be caused by chemotherapy, by radiotherapy, by HIV/AIDS or by a neuroendocrine tumor (e.g. a carcinoid tumor or a Vasoactive Intestinal Peptide (VIP) secreting adenoma) or due to graft-versus-host disease, irritable bowel syndrome (IBS), inflammatory bowel disease (which includes conditions that cause the gut to become inflamed, such as Crohn's disease and ulcerative colitis), coeliac disease (also termed celiac sprue), chronic pancreatitis, diverticular disease, endocrine disorders, vasculitis, post-surgical diarrhea, carbohydrate malabsorption syndrome, amyloidosis, lactose intolerance, small bowel bacterial overgrowth, hepatobiliary disorders, inadequate luminal bile acid, bile acid malabsorption, loss of regulated gastric emptying, pancreatic exocrine insufficiency or neoplasia e.g. bowel cancer or may be due to be due to invasive infectious disease and/or bacterial endotoxins e.g. cholera. See Juckett, G. (2011) Evaluation of chronic diarrhea.84(10).

Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. Like somatostatin, it is a potent inhibitor of growth hormone, glucagon, insulin, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide. It also suppresses LH response to GnRH and decreases splanchnic blood flow.

By virtue of these pharmacological actions, octreotide has been used to treat symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea). Octreotide may be used to treat flushing and/or diarrhea associated with other diseases as described herein. See Szilagyi et el (2002) Aliment. Parmacol. Ther. 15,1889-1897.

Dumping syndrome occurs when food, especially sugar, moves too fast from the stomach to the duodenum—the first part of the small intestine—in the upper gastrointestinal (GI) tract. This condition is also called rapid gastric emptying. Dumping syndrome has two forms, based on when symptoms occur: early dumping syndrome, which occurs 10 to 30 minutes after a meal and late dumping syndrome, which occurs 2 to 3 hours after a meal. Dumping syndrome is caused by problems with the storage of food particles in the stomach and emptying of particles into the duodenum. Early dumping syndrome results from rapid movement of fluid into the intestine following a sudden addition of a large amount of food from the stomach. Late dumping syndrome results from rapid movement of sugar into the intestine, which raises the body's blood glucose level and causes the pancreas to increase its release of the hormone insulin. The increased release of insulin causes a rapid drop in blood glucose levels (hypoglycemia). People who have had surgery to remove or bypass a significant part of the stomach are more likely to develop dumping syndrome. Some types of gastric surgery, such as bariatric surgery, reduce the size of the stomach. As a result, dietary nutrients pass quickly into the small intestine. Other conditions that impair how the stomach stores and empties itself of food, such as nerve damage caused by esophageal surgery, can also cause dumping syndrome.

Short bowel syndrome (also termed SBS or short gut syndrome or simply short gut) is a malabsorption disorder caused by the surgical removal of the small intestine for the treatment of GI conditions (e.g., severe Crohn's disease, traumatic injury, cancer) or more rarely due to the complete dysfunction of a large segment of bowel due to diseases that directly disrupt small intestine nutrient absorption (e.g., chronic intestinal pseudo-obstruction syndrome, refractory sprue).

SBS patients suffer from impaired nutrient absorption that may lead to malnutrition, diarrhea, cramping, bloating, heartburn, weakness, and fatigue. Symptom severity is dependent on the length and functionality of remaining bowel. Nutrient deficiencies may be specific to the section of the bowel that is removed. SBS significantly impacts the patient's quality of life and it is expensive to manage given potential requirements for supplemental nutrition. Parenteral nutrition requires 8-12-hour IV infusions.

Most cases of SBS are acquired, although some children are born with a congenital short bowel. SBS usually does not develop unless more than two thirds of the small intestine has been removed. Physicians segment SBS patients for management based on the length of remaining functional intestine, as follows:

Current drug treatment of short bowel syndrome can include teduglutide (Gattex®) and/or L-glutamine and/or somatropin (human growth hormone). It can also include histamine2-receptor agonists (H2 blockers), proton pump inhibitors (PPIs) and clonidine. See Byrne et al (1995) J. of Parenteral and Enteral medicine, 19 (4): 296-302; Jeppesen et al (2005) Gut 54:1224-1231 and Parrish et el (March 2015) Practical Gastroenterology, 28-42.

Chemotherapy-induced diarrhea (CID) and radiation-induced diarrhea occur as a result of various types of gastrointestinal insults and injuries that are associated with prolonged treatment. Diarrheal conditions may be a consequence of the toxic effect of chemotherapeutics and/or radiotherapy on the gastrointestinal tract, or an inflammatory condition caused by damaged and/or modified gut flora. Gastrointestinal complications due to chemotherapy and radiotherapy are largely inflammatory by nature and include: panenteritis, enterocolitis, mucositis (broadly defined inflammation within the bowels and small intestine); abdominal pain (localized pain in the gastrointestinal system); autoimmune colitis (autoimmune bowel disease characterized by inflammation); ischemic colitis (inflammation of bowel as a result of inadequate blood supply); and gastrointestinal leukocytoclastic vasculitis (inflammation of bowel due to small-vessel vasculitis).

Chemotherapy-induced diarrhea and radiation-induced diarrhea are characterized as a side-effect of pelvic or abdominal radiotherapy and as a side-effect of wide variety of chemotherapeutics, including antimetabolites, plant alkaloids, cytotoxic antibodies, and alkylating agents. Chemotherapy-induced diarrhea is most commonly caused by fluoropyrimidines, particularly fluorouracil (FU), capecitabine and irinotecan.

HIV/AIDS-induced diarrhea includes diarrhea as a secondary manifestation of HIV infection, immunodeficiency, HIV-related enteropathy or medication side effects.

Thousands of patients have neuroendocrine tumors that originate in the gastrointestinal tract and metastasize or spread to the liver or other organs. Overproduction of serotonin within these metastatic neuroendocrine tumor (mNET) cells is a driver of carcinoid syndrome, which is characterized by debilitating diarrhea, facial flushing, abdominal pain, heart valve damage, and other serious consequences. Thus carcinoid syndrome is a subset of neuroendocrine tumors that have specific symptomatic manifestations, due to secretion of vasoactive substances into the systemic circulation.

The severe and unpredictable diarrhea associated with carcinoid syndrome has a profound impact on the lives of cancer patients, often preventing them from participating in daily activities. Patients with carcinoid syndrome can live for many years with metastatic cancer, requiring the need for long-term treatment options to effectively manage their disease

The current standard of care for carcinoid syndrome is somatostatin analog depot injection (SSA), first approved in 1998. SSA is also termed somatostatin receptor ligand (SRL). SRL injection therapy fails over time to maintain adequate control of carcinoid syndrome for most patients, with many becoming not adequately controlled within the first two years after the therapy is initiated. This decrease in response to a drug after its administration is termed tachyphylaxis.

There are three main types of neuroendocrine tumors, classified by origin of the tumor endocrine cells—pancreatic neuroendocrine tumors, gastrointestinal neuroendocrine tumors and pulmonary tumors. A pancreatic neuroendocrine tumor which secretes vasoactive intestinal peptide (VIP) is called VIPoma.

Neuroendocrine tumors and carcinoid syndrome and the medical treatments employed in the treatment of these conditions are described in the literature eg Kloppel et al 2004, Ann. N.Y. Acad Sci 1014:13-17; Strosberg (2014) Endocr. Prac. 20(2);167-175; Oberg et al 2004, Annals of Oncology 15:966-973; Oberg et al 2012, Annals of Oncology 23 (Supplement 7): vii124-vii130; Schmidt et al (2011) Oncogene,30:1497-1505.

Drug treatment of NET: Somatostatin receptor ligand (SRL) therapy remains the backbone of therapy for patients with NET, and patients are generally treated with long-acting octreotide; injectable lanreotide has also been recently used.

If metastasis of carcinoid tumor has occurred and in cases where surgical excision is not suitable, NET may treated be treated with currently recommended chemotherapy.

Anti tumor agents currently used or in clinical trials to treat or palliate NET include the following: alkylating agents, doxorubicin, fluoropyrimidines e.g. 5-fluorouracil, dacarbazine, actinomycin D, platinum compounds (cisplatin, carboplatin, oxaliplatin), irinotecan, etoposide, streptozotocin (STZ), interferon alfa, interferon gamma, bortezomib (iv/sc) marketed as Velcade®, temozolomide (oral) marketed as Temodar®), bevacizumab, capecitabine and somatostatin analogs with a radioactive load (e.g. octreotide attached to a radioactive load using for example yttrium-90 or 111 indium-labeling agents; one example is Lutathera®. Lutathera (lutetium Lu 177 dotatate) is a Lu-177-labeled somatostatin analog peptide currently in development for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults; see Strosberg et al (2017) New England J Med, 376:2, 125-135. Anti-tumor agents may be chemotherapeutic agents or radiotherapeutic agents. A combination of these chemotherapeutic/anti-tumor agents is typically used e.g. cisplatin/etoposide or streptozotocin/5-fluorouracil/doxorubicin or capecitabine/bevacizumab or temozolomide/capecitabine.

Other therapeutic agents which may be used to treat NET are as follows: an mTOR inhibitor such as everolimus (oral) marketed as Afinitor®), temsirolimus (intravenous) marketed as Torisel®and sirolimus (oral) marketed as Rapamune®; an oral VEGFR inhibitor such as sunitinib (marketed as Sutent®); an Src kinase inhibitor (also termed a tyrosine kinase inhibitor) e.g. bosutinib, administered orally, marketed as Bosulif®; and a tryptophan hydroxylase inhibitor e.g. telotristat etiprate also termed LX1032, administered orally. Sunitinib (sunitinib malate) is a targeted tyrosine kinase inhibitor able to inhibit members of the receptor tyrosine kinases families containing a split-kinase domain; these families include VEGF receptor (VEGFR) types 1, 2 and 3 and other receptors. Telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome

Chemoembolization of the hepatic artery for treatment of metastatic carcinoid tumor has been widely used in adults for treatment of NET. Other treatments, which may also be considered as required, include liver-directed therapy, such as radiofrequency ablation, radioembolization, chemoembolization, and rarely surgical debulking.

Breakthrough NET symptoms (due to hormonal symptoms associated with NETs) are common phenomena in patients receiving injectable octreotide e.g. octreotide LAR (long-acting formulation). See for example Dasari, November 2014 Oncology Initial Treatment of Well-Differentiated Neuroendocrine Tumors. Patients may require short-acting octreotide in addition to octreotide LAR, typically 100-250 μg up to 3 times per day for breakthrough symptoms, especially for the first 10 to 14 days after LAR injection while awaiting therapeutic levels. In patients with progressive or poorly controlled symptoms, somatostatin analog doses may be increased as needed. These additional daily s.c. injections may be effective in controlling the breakthrough symptoms, yet significantly increase the physical, emotional, and financial burden of the treatment.

The current invention includes the treatment of patient suffering from NET or any of the diseases described herein by treatment with an oral SRL e.g. octreotide, optionally in combination with one or more other therapeutic agents. Another aspect of the invention is the use of oral octreotide administered in addition to long-acting SRLs or other therapies to prevent or treat breakthrough symptoms. This “rescue therapy” may be given on a regular basis towards the beginning or end of the four-week dosing interval or on an “on demand basis” when symptoms such as diarrhea, facial flushing or abdominal pain occur. The breakthrough symptoms (e.g. in the case of carcinoid syndrome or small bowel syndrome) may be an increase in number or volume of stools.

The current invention includes the treatment of NET by treatment with an oral SRL e.g. oral octreotide in combination with one or more other therapeutic agents. Options include (a) oral SRL in combination with one or more of the anti-tumor (chemotherapeutic or radiotherapeutic) agents as listed above; (b) oral SRL in combination with an mTOR inhibitor e.g. everolimus, temsirolimus or sirolimus (c) oral SRL in combination with a VEGFR inhibitor e.g. sunitinib; (d) oral SRL in combination with a Src kinase inhibitor e.g. bosutinib; (e) a tryptophan hydroxylase inhibitor (also known as a serotonin synthesis inhibitor) e.g. telotristat etiprate; and (f) oral SRL in combination with an injectable SRL.

The oral SRL may be oral octreotide, lanreotide or pasireotide or an oral formulation of DG3173; DG3173 is also termed somatoprim, and is a novel SRL, administered as subcutaneous bolus injections.

One measure of the success of the treatment, comprising oral octreotide in combination with a second or third therapeutic agent, is a reduction in the average number of daily bowel movements of the subject suffering from NET after some weeks of treatment e.g. 6-12 weeks compared with baseline.